1. Field of Invention
This invention relates to ophthalmic or dermatological compositions for external use, and more specifically, to such external medicines when used for the purpose of mediating healing of injured ocular tissue or treating ophthalmic diseases with ophthalmic compositions containing vitamin D (ergocalciferol or cholecalciferol), or for the purpose of protecting ocular tissue or skin from harmful ultraviolet rays with ophthalmic or dermatological compositions containing vitamin D or vitamin K.
2. Description of the Related Art
Vitamin D2, which is refined from vitamin D1 containing other isomers and is highly antirachitic, and vitamin D3, which was researched after vitamin D2, are often used today for the treatment of patients suffering from rickets, osteomalacia, osteoporosis, osteatis fibrosa, osteosclerosis and other bone diseases, malignant tumors such as breast and colon cancers, and skin diseases such as psoriasis. In general, the term "vitamin D" by itself is used to refer to highly antirachitic vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol).
In general, the ultraviolet (UV) light absorption spectra of vitamin D and active vitamin D have absorption maxima near 265 nm, with molar absorption coefficients of about 18,000. Their UV light absorption bands are in the 240-290 nm range. For example, ergocalciferol, 25-monohydroxyvitamin D2, 1alpha,25-dihydroxyvitamin D2, 24,25-dihydroxyvitamin D2 and others have UV light absorption spectra with maxima near 265 nm, and molar absorption coefficients of about 18,900. In addition to these vitamins, provitamin D and previtamin D also have similar UV light absorption spectra. The provitamins D ergosterol and 7-dehydrocholesterol have respective molar absorption coefficients of 11,000 and 10,920, and UV light absorption spectra with maxima at 271, 281 and 293 nm. The previtamins D pre-ergocalciferol and pre-cholecalciferol both have molar absorption coefficients of 9,000 and UV light absorption spectra with absorption maxima at 260 nm.
Therapeutic vitamin D is administered orally or by injection, and is applied to the skin as an active vitamin D ointment in the case of skin conditions. It is known that the molecular structure of vitamin D is altered in the liver and kidneys, converting it into biologically active vitamin D. Hitherto it has been thought that the topical human use of the vitamins D ergocalciferol or cholecalciferol was useless for the treatment of local tissue, as for the treatment of psoriasis, for example.
Since the discovery of calcitriol (1alpha,25-dihydroxycholecalciferol), an active form of vitamin D which is derived from cholecalciferol, it has come to be understood that vitamin D has physiological actions other than calcium regulation. Active vitamins D formed by hydroxylation of the C1 position of the A-ring of the sterol nucleus, side-chain C25 or both C1 and C25 include calcitriol (1alpha,25-dihydroxyvitamin D), 1alpha,24-dihydroxyvitamin D, alfacalcidol (1alpha-monohydroxyvitamin D), calcifediol (25-monohydroxyvitamin D), 1alpha,24,25-trihydroxyvitamin D, 1beta,25-dihydroxyvitamin D, oxacalcitriol, calcipotriol and KH1060. Analogues include dihydrotachysterol. It is now known that there are active vitamin D receptors in the cells, and the inhibition of cell activity is being studied since active vitamin D inhibits the production of a variety of cytokines.
The known ophthalmic symptoms of vitamin deficiency include nyctalopia, Bitot's spots of the conjunctiva and xerosis of the conjunctiva and cornea resulting from vitamin A deficiency, beriberi amblyopia resulting from vitamin B1 deficiency, and diffuse superficial keratitis, retrobulbar neuritis and optic atrophy occurring in cases of vitamin B2 deficiency, as well as hemorrhaging of the eyelid, conjunctiva and retina which are seen in cases of scurvy resulting from vitamin C deficiency.
Hyperplasia occurs in the cells of the keratitis site during the process of wound recovery in postoperative corneal surgery patients, and in some cases the metabolites of hyperplastic cells may also cause corneal opacity and changes in corneal refraction. Although there are normally 5 layers of epithelial cells in the cornea, the corneal epithelium which covers the stroma may grow to about 10 layers of cells if trauma is complex and reaches into the keratocytes. When trauma reaches into the stroma, the activated keratocytes form hyperplasia and produce excess metabolites to speed healing. Although the stratified epithelial cells eventually return to normal, corneal refraction and transparency are affected by transient epithelial stratification and the metabolites of the stratified cells and activated keratocytes. Although corticosteroids are administered following corneal surgery, steroid-induced glaucoma and steroid-induced cataracts are known to occur as side-effects. Surgeries to repair an injured cornea and ophthalmic surgeries which traumatize the cornea include surgery to correct corneal refraction, cataract surgery, intraocular-lens implant surgery, pterygium surgery, surgery to remove a corneal foreign body, corneal transplantation and corneoplasty.
Corneal dystrophy occurs when metabolic abnormalities of the epithelium, keratocytes or endothelium result in the accumulation mainly of isomeric proteins in the keratocytes, causing corneal opacity. Types of corneal dystrophy include granular corneal dystrophy, macular corneal dystrophy, lattice corneal dystrophy, gelatinous drop-like dystrophy, Schnyder's corneal dystrophy and Francois's corneal dystrophy. In corneal ulceration, on the other hand, ulcers are caused by the product of excessive collagenase in the corneal epithelium. Consequently, corneal dystrophy and corneal ulceration differ in their causes and clinical signs.
It is well known that UV light is injurious to the eyes. In particular, wavelengths of 200 to 315 nm can potentially cause actinic keratitis, and in general radiation of 260 nm is known as a cause of teratogenesis and carcinogenesis in the cells. It is also well known that UV light is injurious to the skin. In particular, wavelengths of 200 to 315 nm can potentially lead to sunburn, spots and freckles. UV light at a wavelength of 260 nm is thought to be a cause of skin cancer. Moreover, existing UV blocker should not be used in or around the eyes. The stratospheric ozone layer prevents UV at wavelengths below 286 nm from reaching the surface of the earth. However, the ozone layer is said to be 2-4 mm in thickness under 1 atmosphere, it is reported that fluorine compounds and methyl bromide are destabilizing the ozone layer, and increased rates of skin cancer are being reported from South America and Australia. In general, the peak wavelength of conventional UV sterilizers is 254 nm.
On the first page of the Ocular Surgery News, Vol. 9, No. 11, published in U.S.A. on Jun. 1, 1991, it was reported that patients being treated after excimer laser keratectomy can experience impaired vision and edema caused by UV light.
In corneal disease patients, there is hyperplasia of the cells at the keratitis site, and corneal transparency and refraction may also be adversely affected by the metabolites of such cells. Inflammed keratocytes produce excessive metabolites. Apart from inflammation, there are also corneal diseases in which collagenase and isomeric proteins are seen as metabolites of the corneal epithelial cells and activated keratocytes. The metabolites of stratified cells affect corneal refraction and transparency. It is known that corticosteroids are not effective for treating corneal diseases in which collagenase and isomeric proteins are present. In general, corneal diseases include keratitis, corneal ulceration and corneal dystrophy.
In cataract surgery, generally extracapsular cataract extraction is performed, leaving behind the posterior capsule and the periphery of the anterior capsule. However, cells of the epithelium lentis remain inside the capsule. These residual cells gradually proliferate and spread, and they and their metabolites such as collagen may cause secondary cataracts in which there is opacity of the lenticular capsule and the patient's vision is adversely affected. A two-line drop in test types resulting from such secondary cataracts occurs among approximately 10% of cataract patients within 1 year after surgery, and among approximately 20% of patients within 2 years after surgery.
Keratoconjunctival dryness, also known as "dry eye," is a focus of dispute among ophthalmologists. In the Japanese medical journal Ganka New Insight 5, published by Medical Review, there is mention of the corneal epithelium, vitamin A deficiency and keratoconjunctivitis sicca, and vitamin D is also mentioned in connection with the epidermis. Keratoconjunctival dryness is discussed extensively in the Japanese journal Dry Eye, published by Nihon Hyoronsha. These sources state that there is a profound connection between vitamin A deficiency and diseases of the corneal and conjunctival epithelium, but they also conclude that abnormalities of the corneal and conjunctival epithelium do not occur clinically in vitamin D deficiency, and that vitamin D is not involved in the eye. The journal Dry Eye classifies "dry eye" into two separate conditions, decreased lacrimation and keratoconjunctivitis sicca, which are caused respectively by reduced lacrimation and damage to the cornea and conjunctiva. It is thought that keratoconjunctival dryness is caused partly by environmental factors including decreased nictation while watching a computer or television screen, windy days, dusty environments, ozone and nitrogen oxides. It is said that keratoconjunctival dryness occurs when some factor causes keratinization of the corneal epithelial cells, the conjunctival goblet cells and the nongoblet epithelial cells. As a result, either tears are not retained in the cornea and conjunctiva, or else an abnormal decrease in one of the three layers that form the tears (the mucin layer, lacrimal layer and oil layer) occurs as a result of inflammation of the cornea or conjunctiva, resulting in keratoconjunctival dryness. Conventional treatments for keratoconjunctival dryness include artificial tears, dry eye glasses, Chinese medicine and lacrimal punctal plugs.
Among its other effects, vitamin K acts as a blood coagulation factor. Recently the association between vitamin K and bone metabolism action is being studied. Also, it has been reported that vitamin K amplifies the bone metabolism action of vitamin D3. Vitamin K has a UV absorption band in the 240-270 nm range and is fat soluble. Vitamins K2 are the menaquinones, which have repeating side chains. More specifically, vitamin K1 has a molecular weight of 450.7 and UV absorption maxima at 242-269 and 325 nm, while vitamin K2 (menaquinone 7) has a molecular weight of 649.2 and absorption maxima at 243-270 and 325-328 nm.